Can Lipid-Lowering Drugs Reduce the Risk of Cholelithiasis? A Mendelian Randomization Study

Abstract

Background and Aims

Cholelithiasis etiology intricately involves lipid metabolism. We sought to investigate the plausible causal link between genetically proxied lipid-lowering medications—specifically HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors—and cholelithiasis risk.

Methods

Our study utilized two genetic instruments for exposure to lipid-lowering drugs. These instruments encompassed genetic variants linked to low-density lipoprotein (LDL) cholesterol within or in proximity to drug target genes, along with loci governing gene expression traits of these targets. Effect estimates were derived through Inverse-variance-weighted MR (IVW-MR) and summary-data-based MR (SMR) methods.

Results

Higher HMGCR-mediated LDL cholesterol levels (IVW-MR, OR = 2.15, 95% CI = 1.58–2.94; P = 0.000) and increased HMGCR expression (SMR, OR = 1.19, 95% CI = 1.04–1.37; P = 0.014) are linked to elevated cholelithiasis risk, suggesting potential benefits of HMGCR inhibition. In contrast, higher PCSK9-mediated LDL cholesterol levels (IVW-MR, OR = 0.72, 95% CI = 0.56–0.94; P = 0.015) and increased PCSK9 expression (SMR, OR = 0.90, 95% CI = 0.82–0.99; P = 0.035) both correlate with lower cholelithiasis risk, indicating that PCSK9 inhibition may elevate this risk. Nevertheless, no substantial link emerged between NPC1L1-mediated LDL cholesterol or NPC1L1 expression and cholelithiasis in both IVW-MR and SMR analyses.

Conclusion

This MR investigation affirms the causal link between the utilization of HMGCR inhibitors and a diminished risk of cholelithiasis. Additionally, it indicates a causal link between PCSK9 inhibitors use and increased cholelithiasis risk. However, no significant correlation was found between NPC1L1 inhibitors use and cholelithiasis risk.

Keywords:

• cholelithiasis
• lipid-lowering drugs
• Mendelian randomization analysis
• HMGCR inhibitors
• PCSK9 inhibitors
• NPC1L1 inhibitors

Abbreviations

MR, Mendelian randomization; GWAS, genome-wide association study; eQTLs, expression quantitative trait loci; LDL, low-density lipoprotein; HMGCR, 3-hydroxy-3-methylglutaryl CoA reductase; PCSK9, proprotein convertase subtilisin/kexin type 9; NPC1L1, Niemann-Pick C1–like 1; IVW, multiplicative random effects inverse variance weighted method; SNP, single nucleotide polymorphisms; OR, odds ratio; SMR, summary-data-based mendelian randomization; HEIDI, heterogeneity in dependent instruments; MR-PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier; MAF, minor allele frequency.

Ethical Approval and Informed Consent

This two-sample Mendelian randomization (MR) study relies on publicly available summary-level data from GWASs (Supplementary Table S1). These studies have received ethical clearance from their respective institutional review boards, and participants have provided informed consent for their involvement. Given that our research exclusively utilized publicly accessible datasets to conduct MR, consultation with the Medical Ethics Committee of Wuhan Jinyintan Hospital confirmed that no further ethics approval was necessary.

Acknowledgments

The authors extend their sincere gratitude to the UKB and FinnGen consortia for granting access to the GWAS summary data utilized in this study. Additionally, we would like to convey our heartfelt appreciation to the patients and investigators whose contributions were instrumental in the eQTLGen Consortium and GTEx Consortium.

Disclosure

The authors declare no conflicts of interest in this work.